The present invention relates to the field of artificial oxygen carriers, particularly as blood substitutes for the human or animal body. In particular, the present invention relates to artificial oxygen carriers based on capsules containing perfluorinated hydrocarbons, particularly nanocapsules.
The present invention particularly relates to artificial oxygen carriers in the form of dispersions that are particularly suitable as blood substitutes for the human or animal body, preferably for the transfusion purposes.
The present invention further relates to the use of these dispersions particularly as blood substitutes for the human or animal body, particularly for transfusion purposes, for example for treating states of blood loss, ischaemic conditions and conditions following reperfusion, and also for other purposes.
The present invention further relates to the use of fluorinated, perfluorinated, hydrocarbons, preferably perfluorocarbons, as artificial oxygen carriers for treatment of the human or animal body, particularly as blood substitutes, preferably for purposes of transfusion or other applications.
Finally, the present invention relates to the use of capsules, particularly nanocapsules, comprising an oxygen-permeable capsule material that contains and/or encloses fluorinated, particularly perfluorinated hydrocarbons, preferably perfluorocarbons, as artificial oxygen carriers, particularly as blood substitutes, but also for other applications.
Blood that is suitable for use in transfusions is a scarce commodity. Blood transfusions are often life-saving operations for accident victims, during surgical procedures, and in the treatment of chronic anaemia. The availability of conserved blood is becoming more and more limited for a number of reasons including infection risks (for example by HIV, prions, hepatitis A, B or C, and others) and falling numbers of people willing to donate blood (see for example Habler, O., Pape, A., Meier, J., und Zwissler, B. (2005) [Artificial oxygen carriers as an alternative to blood transfusion]. Anaesthesist 54, 741-754, and Lowe, K. C. (2006) Blood substitutes: from chemistry to clinic. J Mat Chem 16, 4189-4196).
Moreover, there is increasing evidence to indicate that the function of conserved blood deteriorates markedly, and is demonstrable after just a few days (see for example Riess, J. G. (2001) Oxygen carriers (“blood substitutes”)—raison d'etre, chemistry, and some physiology. Chem Rev 101, 2797-2920; Bennett-Guerrero, E., Veldman, T. H., Doctor, A. Telen, M. J., Ortel, T. L., Reid, T. S., Mulherin, M. A., Zhu , H., Bück, R. D., Califf, R. M., und McMahon, T. J. (2007) Evolution of adverse changes in stored RBCs. Proc Natl Acad Sci USA 104, 17063-17068; also Reynolds, J. C., Ahearn, G. S., Angelo, M., Zhang, J., Cobb, F., und Stamler, J. S. (2007) S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci USA 104, 17058-17062).
Blood transfusions are medical procedures that are carried out very frequently. The supply of oxygen to the organs is by far the most important single function that blood performs; if this supply fails, the victim dies very rapidly. Therefore, the first task in the event of significant blood loss is to ensure the transport of oxygen. This is achieved routinely by the use of erythrocytes from donated blood; these cells contain the protein haemoglobin, which binds oxygen very effectively and releases it to the tissue. However, donated blood is associated with several significant disadvantages: there are not enough donors, and not every recipient can receive any donated blood (incompatibility).
Blood may contain unknown infectious materials (for example viruses among others). Screening for dangerous pathogens is complicated and expensive. And donated blood can only be stored for a limited time.
One efficient solution to this problem is the development of artificial oxygen carriers, which render the use of conserved blood unnecessary, or at least reduce the number of blood transfusions substantially.
Accordingly, research has been conducted for several decades into suitable synthetic substitutes—on the one hand into the use of modified haemoglobin and on the other into the use of perfluorinated hydrocarbon (perfluorocarbons), which have very good binding and releasing properties in respect of oxygen.
Besides the oxygen carriers based on haemoglobin derivatives—the development of which has itself encountered a number of problems (such as scarce resources, contamination with pathogens, immunoreactions, circulatory disorders, toxicity, and others)—development work has been carried out and is continuing with other oxygen carriers, including those based on perfluorinated hydrocarbons, also known as perfluorocarbons (see for example previously cited references, also Dinkelmann, S., and Northoff, H. (2003) Artificial oxygen carriers—a critical analysis of current developments, Anästhesiologie Intensivmed Notfallmed Schmerzther 38, 47-54 and Spahn, D. R., and Kocian, R. (2005) Artificial O2 carriers: status in 2005. Curr Pharm Des 11, 4099-4114).
Perfluorocarbons readily dissolve respiratory gases such as oxygen and carbon dioxide, and they then release them into cavities, that is to say small hollow areas. They are largely chemically inert, colourless and odourless, and are completely non-corrosive. Their physical properties, such as melting and boiling points, vary—like alkanes—according to the length of the chain or the size, of their carbon skeleton. Their highly inert nature and associated inability to be metabolised, are probably the reason why perfluorocarbons are practically completely non-toxic. Perfluorocarbons are extremely hydrophobic, and also lipophobic. Accordingly, they are used in the related art as artificial oxygen carriers—in conjunction with emulsifiers—in the form of emulsions, and the function of emulsifier is fulfilled for example by synthetic polymers or, most recently, by phospholipids (for example lecithin, occasionally together with cholesterol).
The first experiments with perfluorocarbons as artificial oxygen carriers were conducted as early as the 1960s (see for example Clark, L. C, Jr., and Gollan, F. (1966) Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. Science 152, 1755-1756). The basic potential of these compounds for use as oxygen carriers was demonstrated in various experiments, some of which were quite spectacular—mice immersed in perfluorocarbon solutions survived. Major problems associated with the first generation of perfluorocarbon oxygen carriers were the poor stability of the perfluorocarbon emulsions, and side effects associated with the emulsifier used.
The problems were solved by using different perfluorocarbons, such as 1-bromoperfluorooctane (=perfluorooctyl bromide), and lecithin as the emulsifier. Perfluorocarbon preparations of the next generation, such as the preparation Oxygent®, have been used successfully in experiments on animals and clinical studies (see for example Spahn, D. R. (1999) Blood substitutes. Artificial oxygen carriers: perfluorocarbon emulsions. Crit Care 3, R93-97).
However, continued clinical use of perfluorocarbons as artificial oxygen carriers is currently limited essentially by two problems, the causes of which are related: the first problem is the relatively short residence time of perfluorocarbons, amounting to just a few hours, in the vascular system; until now, this has enabled perfluorocarbons to be used for short periods, as an interim measure, but has prevented them from being used as a true alternative to blood transfusions. The second problem is the disturbance it creates for the immune system, and the flu-like symptoms associated therewith as well as the risk of increased vulnerability to infection.
The short residence time in the vascular system and the disruption to the immune system are both due to the fact that the emulsion droplets of the perfluorocarbons absorbed by cells of the reticuloendothelial system. This absorption takes place very rapidly, because the system is extremely extensive, and at the same time, while some functions of the cells of the reticuloendothelial system, such as creating inflammation mediators, are activated by absorbing perfluorocarbons, others, such as combating pathogens, are inhibited.
Regarding more comprehensive details about artificial oxygen carriers, particularly as an alternative to blood transfusions and the drawbacks and risks associated therewith, reference is made in particular to Habler, O., Pape, A., Meier, J., and Zwissler, B. (2005) [Artificial oxygen carriers as an alternative to blood transfusion]. Anaesthesist 54, 741-754 and to Riess, J. G. (2001) Oxygen carriers (“blood substitutes”)—raison d'etre, chemistry, and some physiology. Chem Rev 101, 2797-2920.
The object of the present invention is therefore to provide artificial oxygen carriers, preferably based on fluorinated, particularly perfluorinated hydrocarbons, particularly based on perfluorocarbons, which at least to some degree avoid or at least minimise the cited drawbacks of the related art. In particular, such artificial oxygen carriers should be suitable for or capable of being used for example as “blood surrogate” or “blood substitutes” for conditions during and/or after blood loss by the human or animal body (for example following surgical procedures, accidents, injuries, and the like), or for the prophylactic and/or therapeutic treatment of ischaemic conditions or conditions after reperfusion (“tourniquet” or “reperfusion” syndrome).
The applicant has surprisingly discovered that the object as defined, above may be solved by the use of artificial oxygen carriers based on fluorinated, particularly perfluorinated hydrocarbons, preferably perfluorocarbons, wherein the fluorinated hydrocarbons are surrounded, particularly deposited in an oxygen-permeable capsule material, or are enclosed thereby.